Safety and immunogenicity of a parenterally administered rotavirus VP8 subunit vaccine in healthy adults.

BACKGROUND: The P2-VP8 subunit vaccine for the prevention of rotavirus gastroenteritis is comprised of a truncated VP8 subunit protein from the rotavirus Wa strain (G1[P8]) fused to the tetanus toxin P2 epitope, and adsorbed on aluminum hydroxide for intramuscular administration. METHODS: Three groups of 16 adults were randomized to receive three injections of P2-VP8 (12) or placebo (4) at doses of 10, 30 or 60 µg of vaccine. IgG and IgA antibodies to P2-VP8 were assessed by ELISA in serum and lymphocyte supernatant (ALS). Serum samples were tested for neutralizing antibodies to homologous and heterologous strains of rotavirus. RESULTS: The vaccine was well-tolerated. All vaccine recipients demonstrated significant IgA responses and all but one demonstrated IgG responses; in the 60 µg cohort, geometric mean titers (GMTs) rose 70- and 80-fold for IgA and IgG, respectively. Homologous neutralizing antibody responses were observed in about half of participants in all three dose cohorts; in the 60 µg cohort, GMTs against Wa rose from 128 to 992. Neutralizing antibody responses were robust to P[8] strains, moderate to P[4] strains and negligible to P[6] strains. ALS IgA responses were dose dependent. CONCLUSIONS: The P2-VP8 subunit vaccine was well tolerated and evoked promising immune responses. CLINICAL TRIALS REGISTRATION: NCT01764256.

Economic impact of Lyme disease.

To assess the economic impact of Lyme disease (LD), the most common vectorborne inflammatory disease in the United States, cost data were collected in 5 counties of the Maryland Eastern Shore from 1997 to 2000. Patients were divided into 5 diagnosis groups, clinically defined early-stage LD, clinically defined late-stage LD, suspected LD, tick bite, and other related complaints. From 1997 to 2000, the mean per patient direct medical cost of early-stage LD decreased from $1,609 to $464 (p<0.05), and the mean per patient direct medical cost of late-stage LD decreased from $4,240 to $1,380 (p<0.05). The expected median of all costs (direct medical cost, indirect medical cost, nonmedical cost, and productivity loss), aggregated across all diagnosis groups of patients, was approximately $281 per patient. These findings will help assess the economics of current and future prevention and control efforts.

Active surveillance for acute viral hepatitis in rural villages in the Nile Delta.

BACKGROUND: Acute viral hepatitis is less frequent in Egypt than serum antibody levels suggest. Because acute viral hepatitis has a wide clinical spectrum, we tested the hypothesis that many cases are undetected because of mild illness caused by initial, early-childhood exposure to hepatitis viruses. METHODS: During active case detection among 20,000 inhabitants of rural villages in Egypt, we screened 1715 symptomatic patients for serum alanine aminotransferase (ALT) levels. Viral hepatitis markers were tested in 47 subjects who had ALT levels that were least twice the normal level. RESULTS: Of the 47 individuals tested, 4 children aged 3-5 years had immunoglobulin M (IgM) antibodies to hepatitis A virus (anti-HAV IgM). One also had a possible false-positive result to a test for IgM antibodies to hepatitis E virus. None had serological evidence of acute hepatitis B virus (HBV) infection or hepatitis C virus (HCV) infection. However, 33 of the remaining 43 had active HCV infection, having both antibodies to HCV (anti-HCV) and HCV RNA. Four others anti-HCV without HCV RNA, and 2 others had seroconversion to anti-HCV during follow-up. Two patients who were positive for hepatitis B surface antigen had chronic HBV infection. Only 3 with elevated ALT levels had no evidence of acute or chronic infections with known hepatitis viruses. Immunoglobulin G antibodies to hepatitis E virus was detected in 40 patients. CONCLUSION: Active surveillance covering approximately 50,000 person-years detected only 4 cases of acute HAV infection. Almost all persons with mild symptoms and elevated ALT levels had serological evidence of chronic viral hepatitis, most often associated with HCV. Many of these cases were probably "flare-ups" of HCV infection or incidental illness in patients with chronic HCV infection, but some could have been caused by difficult-to-confirm initial HCV infections. Although serological evidence for exposures was highly prevalent, hepatitis viruses seldom caused acute viral hepatitis in these communities.

Prevalence of and risk factors for hepatitis C in rural pregnant Egyptian women.

Prevalence and risk factors for hepatitis C virus (HCV) infection were studied in 2,587 pregnant women from three rural Egyptian villages in the Nile Delta being admitted to a prospective cohort study of maternal-infant transmission; 408 (15.8%) had antibodies to HCV (anti-HCV) and 279 (10.8%) also had HCV-RNA. Fewer than 1% gave a history of jaundice or liver disease. Risk factors for anti-HCV included increasing age, low socioeconomic status and a history of blood transfusion or injection therapy for schistosomiasis. Sub-analyses after stratification of subjects by village revealed risks associated with specific venues for medical care, having a previous delivery attended by a traditional birth assistant (TBA), receiving medical care in a temporary clinic located in a mosque, overnight admission to a private doctor's clinic, and circumcision by a TBA or a 'health barber'. Our results suggest HCV causes very little detected illness in young adult Egyptian women and some sources of HCV transmission in rural Egypt in the past were associated with the provision of medical care and varied by location. Prevention should be focused on providing appropriate resources and health education should be given to formal and informal health care providers and should be sufficiently broad to adjust for local variations in exposures.

High prevalence of hepatitis E antibodies in pregnant Egyptian women.

The epidemiology of hepatitis E virus (HEV), an enterically-transmitted cause of acute viral hepatitis (AVH), is not fully understood. During outbreaks on the Indian subcontinent and elsewhere, HEV causes severe AVH with mortality rates around 20% during pregnancy. In Egypt, where prevalence of HEV antibodies (anti-HEV) in rural communities is very high, severe HEV-caused AVH in pregnant women has not been reported. This study examined a cohort of 2,428 pregnant women in the Nile Delta to assess prevalence of, and risk factors for, anti-HEV and correlated these with history of liver disease. Anti-HEV prevalence was 84.3%. Several risk factors associated with anti-HEV included older age, many siblings, not using soap to wash produce and frequent contact with cats. History of jaundice and liver disease was rare and not increased in those having anti-HEV. Our results confirm Egypt's high HEV endemicity and show that almost all women of childbearing age in these communities had prior HEV exposures without a history of liver disease. Reasons for the lack of clinical hepatitis remain unclear but could be the result of early childhood HEV exposures, producing long-lasting immunity and/or modify subsequent responses to exposure. Alternatively, the predominant HEV strain(s) in Egypt are less virulent than those in South Asia.

Hepatitis E antibody seroconversion without disease in highly endemic rural Egyptian communities.

Hepatitis E virus (HEV) is enterically transmitted and causes self-limiting acute viral hepatitis (AVH) primarily in less developed countries. A prospective cohort study to assess incidence of, and risk factors for, seroconversion to HEV (anti-HEV) was conducted in two Egyptian villages with a 67.7% anti-HEV prevalence. Nine hundred and nineteen villagers who were initially anti-HEV-negative were followed for 10.7 months. Thirty-four (3.7%) had strong anti-HEV serologic responses at follow-up giving an estimated anti-HEV incidence of 41.6/1,000 person-years. No significant associations were found between anti-HEV seroincidence and demographic and socioeconomic factors, source of water, household plumbing or sanitation, hand and vegetable washing, ownership of animals, jaundice and many other variables. None of the seroconverting subjects gave a history compatible with AVH during the interval. We hypothesize that both zoonotic and anthroponotic transmission of avirulent (possibly genotype-3) HEV is occurring extensively in these rural villages. An alternative explanation for the lack of morbidity among anti-HEV incident cases could be initial asymptomatic infections occur during early childhood with subsequent antibody titer boosting without illness upon re-exposure to the virus.

Intrafamilial transmission of hepatitis C in Egypt.

The incidence of hepatitis C (HCV) infection and associated risk factors were prospectively assessed in a cohort of 6,734 Egyptians from 2 rural villages who were negative for antibodies to HCV (anti-HCV). Initial and follow-up sera were tested for anti-HCV by enzyme immunoassay (EIA), and possible incident cases were confirmed by using the microparticle enzyme immunoassay (MEIA) and tested for HCV RNA. All follow-up serum samples converting from negative to positive without detectable HCV-RNA were further tested by recombinant immunoblot assay. Over an average of 1.6 years, asymptomatic anti-HCV seroconversion occurred in 33 people (3.1/1,000 person-years [PY]), including 28 (6.8/1,000 PY) in the Nile Delta village (AES), where prevalence was 24% and 5 (0.8/1,000 PY) in the Upper Egypt village (baseline prevalence of 9%). The strongest predictor of incident HCV was having an anti-HCV-positive family member. Among those that did, incidence was 5.8/1,000 PY, compared (P < .001) with 1.0/1,000 PY; 27 of 33 incident cases had an anti-HCV-positive family member. Parenteral exposures increased the risk of HCV but were not statistically significant; 67% of seroconverters were younger than 20 years of age, and the highest incidence rate (14.1/1,000 PY) was in children younger than 10 who were living in AES households with an anti-HCV-positive parent. In conclusion, young children would especially benefit from measures reducing exposures or preventing infection with HCV.

Estimation of the risk of transmission of hepatitis C between spouses in Egypt based on seroprevalence data.

BACKGROUND: Transmission of hepatitis C virus (HCV) between spouses could be due to sexual contact, sharing needles, or other routes. There is uncertainty regarding the degree to which HCV is transmitted between spouses. METHODS: Data from a 1997 cross-sectional serological survey of HCV in two communities in Egypt were used to estimate the risk of transmission between spouses by simultaneously modelling the probabilities of community acquisition and spousal transmission of HCV as functions of known predictors. RESULTS: We estimate that the probability of wife-to-husband transmission was 34% (95% CI: 15-49%) and 10% (95% CI: 0-26%) for anti-HCV-positive wives with and without detectable HCV RNA, respectively. The probability of husband-to-wife transmission was estimated to be 3% (95% CI: 0-13%) and 0% (95% CI: 0-9%) for husbands with and without detectable HCV RNA, respectively, at the time of the survey. There was moderate evidence that the probability of wife-to-husband transmission differed from that of husband-to-wife transmission (P = 0.076), and there was greater risk of transmission from those with detectable RNA at the time of the survey (P = 0.046). We estimate that 6% of those infected acquired HCV from their spouse. CONCLUSION: Our study results support the possibility that HCV is transmitted between spouses in Egypt. Further research is needed to identify the exact routes of transmission so that preventive measures can be instituted.

Optimal choice of a cut point for a quantitative diagnostic test performed for research purposes.

Often, in epidemiologic research, classification of study participants with respect to the presence of a dichotomous condition (e.g., infection) is based on whether a quantitative measurement exceeds a specified cut point. The choice of a cut point involves a tradeoff between sensitivity and specificity. When the classification is to be made for the purpose of estimating risk ratios (RRs) or odds ratios (ORs), it might be argued that the best choice of cut point is one that maximizes the precision of estimates of the RRs or ORs. In this article, two different approaches for estimating RRs and ORs are discussed. For each approach, formulae are derived that give the mean squared error of the RR and OR estimates, for any choice of cut point. Based on these formulae, a cut point can be chosen that minimizes the mean squared error of the estimate of interest.

Age-specific prevalence of antibodies to hepatitis A in Santiago, Chile: risk factors and shift in age of infection among children and young adults.

Transition from high to lower endemicity of hepatitis A virus (HAV) infection may portend increased public health burden with the shift of infection to older ages and increasing morbidity and mortality. This report describes age-specific prevalence of antibodies to HAV (anti-HAV) among children and young adults in Santiago, Chile, compared with previous prevalence data and assesses factors predictive for anti-HAV. In 1998, a serosurvey was performed in Metropolitan Santiago, designed to enroll a representative, age-stratified population on the basis of area of residence. A total of 784 individuals (age range, 1-24 years) were enrolled. Anti-HAV prevalence by year of life was as follows: ages 1 to 4, 12.5%; 5 to 9, 26.2%; 10 to 14, 43.4%; 15 to 19, 57.4%; 20 to 24, 73.9%. Adjusting for age, factors associated (inversely) with anti-HAV included residential areas of higher socioeconomic status (SES), parental education, and household characteristics of potable water, municipal sewage system, and the presence of a toilet or refrigerator in the house. In logistic regression analysis, only maternal years of education and residence in areas of higher SES remained independently associated with anti-HAV. Excluding those from higher SES areas, comparison of the age-specific anti-HAV prevalence data from previous studies of similar methodology in areas of lower SES revealed consistent decreases across all age groups; the age-standardized prevalence for this age range (1-24 years) dropped from 53.7% in 1990 to 40.6% in 1998. In light of the growing pool of susceptible individuals at older ages, with HAV continuing to circulate in the communities, evaluation of the feasibility of vaccination programs would be judicious.

Hepatitis c in a community in Upper Egypt: risk factors for infection.

This investigation's objective was to identify risk factors for hepatitis C virus (HCV) in a village in Upper Egypt with a moderately high prevalence (8.7%) of antibodies to HCV (anti-HCV). A representative sample of 6,012 (63%) of the 9,581 village inhabitants was included in the study. A questionnaire solicited information regarding risk factors for infection, and blood samples were tested for anti-HCV. Parenteral risks identified in age-adjusted analysis included blood transfusions, dental procedures, hospital admission, surgery, complicated deliveries, history of injection therapy for schistosomiasis, and history of frequent injections. Circumcision was pervasive and was not associated per se with ant-HCV; however, circumcision by an informal, rather than formal, health care provider was associated with anti-HCV among young men and boys. The results did not reveal any unique community-acquired exposures that caused HCV infections: inhabitants who had tattoos, who smoked goza, who were shaved by a community barber, or who had their ears pierced were not at greater risk for anti-HCV than those who did not. Risks identified in multivariate analysis for both those older and younger than 30 years included prior parenteral therapy for schistosomiasis and blood transfusion; for those 30 or younger, circumcision by an informal rather than formal health care provider, and frequent injections; and for those older than 30, never attending college, invasive medical procedures, and complicated deliveries. Selecting for those with blood transfusion, prior parenteral therapy for schistosomiasis, and invasive medical procedures would identify less than half of those infected. Inclusion of frequent injections would identify 80% of those infected with HCV, but as a result of the pervasive use of injections, it would not discriminate from those uninfected. Nonetheless, general reduction of these exposures and assuring sterile practices are logical goals for intervention.

Comparison of second- and third-generation enzyme immunoassays for detecting antibodies to hepatitis C virus.

Supplemental assays, such as recombinant immunoblot assays (RIBA), are used to confirm detection of antibodies to hepatitis C virus (HCV). However, due to their expense, they are not widely used in developing countries. The purpose of our study was to compare the results of second- and third-generation (G2 and G3, respectively) enzyme immunoassays (EIAs) and to resolve discordant results by using a supplemental assay to assess the reliability of G2 and G3 EIAs to confirm anti-HCV antibody-positive results. We performed both G2 and G3 EIAs for anti-HCV antibodies on 1,134 serum samples collected during the 2nd year of a longitudinal community-based study in Egypt; 35 samples with discordant results were tested by Abbott Laboratories Micro-Particle Immunoassay (M-EIA) and RIBA. Viremia was determined with an in-house nested reverse transcriptase PCR (RT-PCR) to detect HCV RNA. Concordance between the two assays (G2/G3) was 96.9%; 87 (7.7%) samples were positive and 1,012 (89.2%) were negative by both assays. For 17 samples, the discordant results were G2 assay negative and G3 assay positive, and for 18 samples, the discordant results were G2 assay positive and G3 assay negative. Among the 17 G2 assay-negative and G3 assay-positive samples, 15 were M-EIA positive and 7 were PCR positive. Among the 18 G2 assay-positive and G3 assay-negative samples, 2 were M-EIA positive and none were PCR positive. RIBA results from 24 discordant samples showed 87.5% agreement with the G3 EIA, 12.5% agreement with the G2 EIA, and 95.8% agreement with M-EIA. Eleven samples were indeterminate by RIBA and excluded from this analysis. Based on RIBA results, the sensitivity of the G3 EIA was 99%, compared to 89.8% for the G2 EIA, while the specificity of the G3 EIA was 99.8%, compared to 98.9% for the G2 EIA. These results show that the reliability of the G3 EIA in screening these sera is excellent, and the G3 assay can be used in the absence of supplemental tests where resources are limited. RIBA appears not to have advantages over the less expensive M-EIA screening assay. The main disadvantage of RIBA is the occurrence of indeterminate results, especially among problematic samples. Samples giving discordant results in multiple assays are often indeterminate with the RIBA.

Mapping Lyme disease incidence for diagnostic and preventive decisions, Maryland.

To support diagnostic and preventive decision making, we analyzed incidence of Lyme disease in Maryland on the zip code level. Areas of high incidence were identified on the Upper Eastern Shore of the Chesapeake Bay and in counties north and east of Baltimore City. These latter foci, especially, are not visible when mapping Lyme disease on the county level.